1,2,3,11b-tetrahydropyrido-(3,4,5:m,n)thioxanthenes,the acid addition salts thereof

ABSTRACT

1,2,3,11B-Tetrahydropyrido(3,4,5:m,n) thioxanthenes of the formula   WHEREIN X and Y each are H, alkyl of 1-4 carbon atoms or C1 and R is H or alkyl of one to four carbon atoms have psychotropic activity, including tranquilizing, hypnotic, antidepressant and narcosis-potentiating activity.

United States Patent [191 Unger et al.

[451 March 6, 1973 [5 1,2,3, llB-TETRAHYDROPYRIDO- [3,4,5:M,N]THIOXANTHENES, THE ACID ADDITION SALTS THEREOF [75] Inventors: RichardUnger; Helmut Muller-Calgan, both of Darmstadt, Germany [73] Assignee:Merck Patent Gesellschaft mit beschraenkter Haftung, Darmstadt, Germany[22] Filed: Aug. 20, 1970 [21] Appl. No.: 65,680

[30] Foreign Application Priority Data Aug. 22, 1969 Germany ..P 19 42755.5

[52] US. Cl ..260/294.8 A, 260/328, 424/263, 424/266 [51] Int. Cl...C07d 31/50 [58] Field of Search ..260/294,8 A

[5 6] References Cited OTHER PUBLICATIONS Burger, Medicinal Chemistry,Third Edition, Part 2,

Wiley-Interscience Publishers, Page 1439 (1970).

Primary Examiner-Alan L. Rotman Attorney-Millen, Raptes & White 5 7ABSTRACT l,2,3,l lb-Tetrahydropyrido[ 3,4,5:m,n]thioxanthenes of theformula 15 Claims, No Drawings 1,2,3, 1 lB-TETRAIIYDROPYRIDO-[3,4,5:M,N]TI-IIOXANTIIENES, THE ACID ADDITION SALTS THEREOF BACKGROUND OF THEINVENTION This invention relates to novel 1,2,3,llb-

tetrahydropyrido-[ 3,4,5 :m,n]thioxanthenes.

SUMMARY OF THE INVENTION l,2,3,1 lb-Tetrahydropyrido[3,4,5:m,n]thioxanthenes of the formula wherein R is H or alkyl of one to four carbonatoms; X is H, alkyl of one to four carbon atoms, or Cl; and Y is H,alkyl of one to four carbon atoms, or Cl; and the physiologicallyacceptable acid addition salts-thereof have, with a good compatibility,low toxicity, and a wide therapeutic range, psychotropic activity,including one or more of tranquilizing, hypnotic, antidepressant andnarcosis-potentiating activity. Their low muscle-relaxing activity is aparticular advantage of these psychic depressants.

DETAILED DISCUSSION Of the1,2,3,llb-tetrahydropyrido[3,4,5:m,n]thioxanthenes of Formula I,preferred are those of the for- In the process aspect of this inventionl,2,3,l lbtetrahydropyrido[3,4,5:m,n]thioxanthenes of Formula I andtheir physiologically acceptable acid addition salts are prepared bytreating with a cyclizing agent a compound of the formula wherein X andY have the values given above and Z is CI-IO or CH,Q, in which is a freeor reactively esterified OI-I-group. I

In another process aspect, a compound of the formula III wherein R, X,and Y have the values given above is condensed intramolecularly withagents forming thioether bridges.

In still another process aspect a compound otherwise corresponding toFormula I, but which contains in the nitrogen-containing ring one ormore reducible groups, preferably one or more double bonds, especiallyin the 2,3- and/or l,l lb-position or l,2-position, or which contains acarbonyl group in the 1- and/or 3-position and, when a double bond ispresent in the l,2- or 2,3- position, in the form of correspondingquaternary salt, is treated with a reducing agent.

Additionally, a compound of Formula I can be treated with an alkylatingagent and/or is converted into a physiologically acceptable acidaddition salt thereof by treatment with an acid, or a compound ofFormula I in free base form is produced from the acid addition saltthereof by treatment with a base. When R, X and/or Y are alkyl, theypreferably are methyl, ethyl, and n-propyl. They can, however, also beisopropyl, nbutyl, isobutyl, sec.-butyl, and tert.-butyl.

The compounds of Formula I have an asymmetrical carbon atom. Therefore,they are obtained in the form of racemates during the synthesis thereof.These racemates are, in most cases, employed as such. They can, however,be resolved in a conventional manner into the enantiomers thereof bytreatment in free base form with an optically active acid, e.g. tartaricacid,

camphorsulfonic acid, mandelic acid, malic acid, lactic acid, or othersubstances suitable for the resolution of racemates. Such resolution ofracemates can be conducted in the conventional manner employing methodswell known in the literature.

The compounds of Formula I are preferably obtainable by the cyclizationof compounds of Formula II. The residue Q in the compounds of Formula IIcan represent, in addition to a free OI-I-group, chlorine or bromine, oran alkylsulfonyloxy group, preferably containing one to six carbonatoms, e.g. methanesulfonyloxy, or an arylsulfonyloxy, preferably six to10 carbon atoms, e.g. benzeneor especially p-toluenesulfonyloxy. Ingeneral, the residue 0 can represent any reactive group which permitscyclization of a compound of Formula II to form a compound of Formula I.

Preferred starting compounds of Formula II are the thioxanthenes ofFormula II wherein Z is CHO. These compounds can be obtained from theconventional l0- aminomethylthioxanthenes (corresponding to Formula II,Z H) by formylation, e.g., by heating with formic acid, or by reactionwith formic acid esters, such as the methyl ester of fonnic acid, or theethyl ester of formic acid. During the cyclization of such compounds,there are obtained, in addition to the desired compounds of Formula I,equal amounts of compounds of Formula IVa below, by disproportionation,which latter compounds can be converted into compounds of Formula I asdescribed hereinbelow.

Starting compounds of Formula II wherein Z is CI-I Q are preferablyproduced in situ by reacting the conventionallO-aminomethylthioxanthenes otherwise corresponding to Formula IIwherein Z is H in a suitable solvent with formaldehyde or a compoundyielding formaldehyde, e.g., polyoxymethylene, paraformaldehyde orformaldehyde dimethylacetal, and, optionally thereafter esterifying thethus-obtained compounds of Formula II (Q=OH) with a reactive acid. Forthe esterification, hydrochloric acid, hydrobromic acid,methanesulfochloride, p-toluene-sulfochloride, or benzenesulfochloridecan be employed.

The compounds of Formula II can be cyclized with acidic catalysts toobtain compounds of Formula I. Preferred catalysts are mineral acids,e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, polyphosphoric acid, PCl PCl POCl organic sulfonic acids e.g.,toluenesulfonic acid and camphorsulfonic acid; Lewis acids, e.g.aluminum chloride, boron fluoride and zinc chloride, and acidic salts,e.g., potassium hydrogen sulfate.

The cyclization can be conducted in the presence of an additionalsolvent, for example, a lower alcohol, e.g., methanol and ethanol, anether, e.g. dioxane and tetrahydrofuran, an ester, a carboxylic acid,e.g. acetic acid, a hydrocarbon, e.g. tetrahydronaphthalene, benzene andtoluene, nitrobenzene, a chlorinated hydrocarbon, e.g., methylenechloride and chloroform; concentrated hydrochloric acid, or mixtures ofsuch solvents. It is also possible to employ an excess of the cyclizingagent as the reaction solvent.

The cyclization can be conducted at temperatures of between and 300 C.The reaction can be accelerated by heating, optionally up to the boilingpoint of the solvent employed. The reaction time is several minutes toseveral days. When Z is a formyl group, polyphosphoric acid ispreferably employed as the catalyst in the cyclization reaction.However, the other above-mentioned reaction conditions likewise resultin a reaction mixture from which the compounds of Formula I can beisolated, e.g., chromatographically.

As stated above, the compounds of Formula I are also obtainable by theintroduction of a thioether bridge into compounds of Formula Ill. Thecompounds of Formula II] can be prepared, for example, by thecyclization of N-formyl-2,2-diphenyl-l-aminoethanes, optionallysubstituted on the phenyl rings, with polyphosphoric acid and subsequentreduction of the thus-obtained 3,4-dihydro-4-phenylisoquinoline tocompounds of Formula [II wherein R is H. Alkylation of the nitrogen atomcan be conducted in accordance with conventional methods to producecompounds of Formula II wherein R is an alkyl group of one to fourcarbon atoms. Preferred starting compounds of Formula III are thosewherein X and Y, respectively, are hydrogen.

Suitable agents which form thioether bridges are sulfur dichloride,disulfur dichloride, sulfur, and all agents which split off sulfur underthe reaction conditions, such as, for example, sulfides, polysulfidesand thiosulfates. The use of Friedel-Crafts type catalysts isadvantageous, e.g., aluminum chloride, boron fluoride and lithiumbromide, or the etherates or alcoholates thereof. However, the reactioncan also be conducted with other catalysts or without catalyst.

The compounds of Formula I can also be obtained by reducing compoundsotherwise corresponding to Formula l, except that they contain at leastone double bond or a carbonyl group in the nitrogen-containing ring,especially by reducing compounds of the formulas LII KO Y X Y Li T N T RIVn IVb IVc Compounds of Formulas Na and IVc can also be present in theform of the quaternary ammonium salts lVd and IVe IVd IVO In FormulaslVa lVe X, Y and R have the values given above, and V represents an acidresidue.

The starting compounds of Formula lVa can be prepared, for example, bycyclizing compounds of Formula ll wherein Z is a formyl group, in themanner described above. By disproportionation, equal portions of thecompounds of Formulas] and IVa are produced. The compounds of FormulalVa can be separated and can then be reduced to compounds of Formula I,or the entire reaction mixture can be treated with a reducing agent,thus reducing the compounds of Formula lVa to compounds of Formula Iwithout isolating them.

The compounds of Formula lVa can also be prepared by treating compoundsof the formula wherein R, X, and Y have the values given above, and W isCl, methoxy, or ethoxy. Compounds of Formula VI are obtained by reactingthe corresponding aminomethylthioxanthenes with phosgene, methylchloroformate, or ethyl chloroformate.

The starting compounds of Formula lVc can be prepared by cyclizingcompounds of Formula II wherein Z is CHO under mild conditions.

The reduction of these compounds, especially those of Formulas IVathrough We, is preferably conducted by catalytic hydrogenation or bytreatment with a complex metal hydride. Suitable catalysts for thehydrogenation step are, for example, noble metal, nickel, and cobaltcatalysts, as well as copper chromium oxide. The noble metal catalystscan be utilized in the form of supported catalysts, such as, forexample, palladium or charcoal, calcium carbonate, or strontiumcarbonate, as oxide catalysts, such as, for example, platinum oxide, oras finely divided metal catalysts. Nickel and cobalt catalysts aresuitably employed as Raney metals, and nickel is also employed onkieselguhr or pumice as the support.

The hydrogenation can be conducted at room temperature and under normalpressure, or also at an elevated temperature and/or increased pressure.Preferably, the reaction is conducted at pressures of between I and 200atmospheres and at temperatures of between 80 C. and +l50 C. Suitably,the reaction is conducted in the presence of a solvent, e.g. methanol,ethanol, isopropanol, ethyl acetate, dioxane, glacial acetic acid,tetrahydrofuran, or water. In some cases, the addition of a mineral acidis advantageous, for example hydrochloric or sulfuric acid. For thehydrogenation step, the free bases, e.g. [Va and We, the acid additionsalts thereof, or the quaternary salts Nd and We can be employed. Duringthe hydrogenation, care should be taken that the benzene rings are notlikewise reduced. Consequently, the process is preferably conducted sothat the hydrogenation is terminated after the absorption of thestoichiometric amount of hydrogen.

As stated above, advantageous reducing agents are also the complex metalhydrides, such as, in particular, LiAlI-I, and NaBI-l optionally withthe addition of catalysts, e.g. BF AICI or LiBr. These reducingreactions are suitably conducted in the presence of an inert solvent,e.g., tetrahydrofuran, ethylene glycol dimethyl ether, or pyridine. Whenusing NaBI-I the reaction can also be conducted in aqueous or alcoholicsolutions. The reduction is preferably carried out between -80 C. andthe boiling point of the solvent employed, preferably between 0 and 100C. The thus-formed metal complexes can be decomposed, for example, withmoist ether, an aqueous ammonium chloride solution, or aqueous alkalihydroxide solutions, preferably in equivalent amounts.

The compounds of Formula I can be converted into acid addition salts,preferably the physiologically acceptable acid addition salts thereof bytreatment with acids. Suitable acids for this reaction are thoseyielding physiologically compatible salts.

For this purpose both organic and inorganic acids can be employed suchas, for example, aliphatic, alicyclic, araliphatic, aromatic, orheterocyclic monoor polybasic carboxylic or sulfonic acids, such asformic acid, acetic acid, propionic acid, pivalic acid, diethylaceticacid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid,aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid,phenylpropionic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methanesulfonic acid,ethanedisulfonic acid, naphthalenemonoand -disulfonic acid, sulfuricacid, nitric acid, hydrohalic acids, such as hydrochloric or hydrobromicacid, and the phosphoric acids, e.g. orthophosphoric acid. Other acidscan be used to produce other acid addition salts for resolution,isolation, characterization and/or purification purposes.

The compounds of this invention are useful for inducing a psychicdepressant effect in living beings, especially mammals. They can be usedin the same manner as known thioxanthenes having tranquilizing,hypnotic, antidepressant and/or narcosis-potentiating activity.

The novel compounds can be employed in a mixture with solid and/orliquid and/or semi-liquid excipients in the human or veterinarymedicine. Suitable carriers are such organic or inorganic substanceswhich are suitable for parenteral, enteral, or topical application andwhich do not react with the novel compounds, such as, for example,water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose,magnesium stearate, talc, vaseline, cholesterol. For parenteralapplication, especially suitable are solutions, preferably oily oraqueous solutions, as well as suspensions, emulsions, or implants.Furthermore, advantageous for enteral application are tablets, dragees,syrups, and juices, and for topical application, salves, creams, orpowders. The above-mentioned preparations can optionally be sterilizedor mixed with auxiliary substances, such as preservatives, stabilizers,or wetting agents, salts for influencing the osmotic pressure, buffers,coloring, flavoring, and/or aromatous substances.

The substances of this invention are preferably administered in a dosageof l 500 mg. per dosage unit, preferably in admixture with l 5000 mg. ofa pharmaceutical carrier.

In the following examples, the temperatures are set forth in degreescentigrade.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE] a. g. of l0-formylaminomethyl-thioxanthene (m.p. l30l3l;obtainable by boiling l0- aminomethyl-thioxanthene with formic acid intoluene for 12 hours) is added to a mixture which was previously stirredfor 4 hours at consisting of 524 g. of phosphorus pentoxide and 404 g.of 89 percent phosphoric acid. Within 30 minutes, the reaction mixtureis heated, under agitation, to 200; this temperature is maintained for 2hours, and then the mixture is cooled to 100. After the dropwiseaddition of 560 ml. of water and I850 ml. of 47 percent potassiumhydroxide solution, the reaction mixture is allowed to cool to roomtemperature, and extracted with chloroform. The chloroform solution (A)is dried and evaporated. By means of column chromatography, l,2,3,llbtetrahydropyrido[3,4,5:m,n]-thioxanthene is isolated from the reactionmixture and precipitated as the hydrobromide by means of ethanolichydrobromic acid. After boiling out with ethanol, vacuum-filtering, anddrying, 1,2,3,l lb-tetrahydropyrid[3,4,5 :m,n]thioxanthene hydrobromideis obtained, m.p. 305. Furthermore, pyrido[3,4,5:m,n]thioxanthene, m.p.146, is obtained from the reaction mixture.

Analogously, by treatment with polyphosphoric acid, there are obtainedfrom:

2-chloro-l0-formylaminomethyl-thioxanthene (m.p. 126) 2-methyll0-formylaminomethyl-thioxanthene2,8-dichloro-l0-formylaminomethyl-thioxanthene 2 ,8-dimethyl-l0-formylaminomethyl-thioxanthene the following compounds:4-chloro-1,2,3,l lb-tetrahydropyrido[ 3,4,5:m,n]thioxanthene (m.p.109-110; hydrobromide, m.p. 309-3l 0) l0-chloro-1 ,2,3,1lb-tetrahydropyrido[3,4,5:m,n,] thioxanthene (hydrobromide, m.p. 306;methanesulfonate, m.p. 229) 4-methyl-1 ,2,3,1 lb-tetrahydropyrido[ 3,4,5 :m,n]thioxanthene l0-methyl-l,2,3,1lb-tetrahydropyrido[3,4,5:m,n]thioxanthene 4,10-dichloro-l ,2,3,l lb-tetrahydropyrido[3,4,5;m,n]

thioxanthene 4,10-dimethyl-l ,2,3,l lb-tetrahydropyrido[3,4,5:m,n]thioxanthene and, as byproducts, the following compounds are obtained:

4-chloropyrido[3,4,5:m,n]thioxanthenel0-chloropyrido[3,4,5:m,n]thioxanthene4-methylpyrido[3,4,5:m,n]thioxanthene l0-methylpyrido[ 3 ,4,5 :m,n]thioxanthene 4,l0-dichloropyrido[3,4,5:m,n]thioxanthene4,10-dimethylpyrido[3,4,5:m,n]thioxanthene2-Chloro-lO-formylaminomethylthioxanthene (m.p. 126) can be prepared byreacting 5-chloro-2-mercaptobenzoic acid, benzene, and sulfuric acid to2- chlorothioxanthone (m.p. l53l54), reducing the latter withphosphorus/hydrogen iodide to 2-chlorothioxanthene (m.p. 99l00),stepwise treatment with butyllithium carbon dioxide(2-chlorothioxanthenecarboxylic acid; m.p. 200), thionyl chloride,ammonia (2- chlorothioxanthene-IO-carboxylic acid amide; m.p. 184),lithium aluminum hydride/aluminum chloride,

hydrobromic acid (2-chloro-10-aminomethyl-thioxanthene hydrobromide;m.p. 276277), and boiling with formic acid in toluene.

Analogously, 2-methyl-lO-formylaminomethylthioxanthene is obtained,starting with S-methyI-Z-mercaptobenzoic acid.

b. Five grams of 1,2,3,llb-tetrahydropyrido[3,4,5 :m,n]-thioxanthene, 30ml. of formic acid, 1.1 g. of sodium formate, and 4.3 ml. of 35 percentaqueous formaldehyde solution are mixed together, heated for 3 hours to60, and then boiled overnight. Then, the reaction mixture is evaporated,the residue taken up in dilute hydrochloric acid, and the solutionwashed with ether. The acidic, aqueous phase is made alkaline andextracted with ether. After the addition of ethanolic hydrobromic acid,vacuum-filtering, and drying, 2- methyl- 1 ,2,3,1 lb-tetrahydropyrido[3,4,5:m,n]thioxanthene hydrobromide is obtained, m.p. 24l-242.Analogously, by precipitation with ethanolic methanesulfonic acid,2-methyl-1,2,3,1 1btetrahydropyrido[3,4,5:m,n]thioxanthenemethanesulfonate is obtained, m. p. 218.

From

Z-methyl-lO-chloro-l ,2,3,l lb-tetrahydropyrido[ 3,4,5:m,'n]thioxanthene, methanesulfonate, m.p. 194-195 2,4-dimethyl-l,2,3,l lb-tetrahydropyrido[ 3 ,4,5 :m,n] thioxanthene 2,10-dimethyl-l,2,3,l lb-tetrahydropyrido[3,4,5:m,n] thioxanthene2-methyl-4,l0-dichloro-1,2,3,l 1btetrahydropyrido[3,4,5:m,n]thioxanthene2,4, l O-trimethyl-l ,2,3 ,l lb-tetrahydropyrido[3,4,5:m,n]cthioxanthene, and the salts thereof.

c. 8.8 g. of l,2,3,l lb-tetrahydropyrido[3,4,5 :m,n]thioxanthene isdissolved in 30 ml. of acetonitrile, and 2 g. of ethyl bromide is addedthereto. After allowing the reaction mixture to stand overnight, etheris added thereto, whereupon unreacted starting material precipitates asthe hydrobromide; this latter compound is vacuum-filtered. The filtrateis evaporated, the

residue is dissolved in ether, and ethanolic hydrobromic acid is added.The thus-precipitated hydrobromide is recrystallized from ethanol/ether,the product being 2-ethyl-1,2,3,llb-tetrahydropyrido[3,4,5:m,n]thioxanthene hydrobromide, m.p. 236.

Analogously, the following compounds can be prepared: 2-n-propyl-l,2,3,l lb-tetrahydropyrido[3 ,4,5 :m,n] thioxanthene hydrobromide, m.p.216; 2-isobutyl-l ,2,3,l lb-tetrahydropyrido[3,4,5:m,n] thioxanthenehydrobromide, m.p. 234.

EXAMPLE 2 a. 53 g. of pyrido[3,4,5:m,n]thioxanthene, m.p. 146, obtainedaccording to Example 1(a) as a by-product, is added to a mixture of 10g. of lithium aluminum hydride and 67 g. of anhydrous aluminum chloridein 800 ml. of absolute ether, and boiled for 15 hours. Thereafter, asolution of 71 g. of sodium hydroxide in 200 ml. of water is carefullyadded thereto, the reaction mixture is vacuum-filtered from the aluminumhydroxide granules, washed with ether, and the hydrobromide isprecipitated from the ether solution by the addition of ethanolichydrobromic acid, thus obtaining 1,2,3,l1b-tetrahydropyrido[3,4,5:m,n]thioxanthene hydrobromide, m.p. 305.

From: 4-chloropyrido[ 3 ,4,5 :m ,nlthioxanthene10-chloropyrido[3,4,5:m,n]thioxanthene4-methylpyrido[3,4,5:m,n]thioxanthenel-methylpyrido[3,4,5:m,n]thioxanthene4,10-dichloropyrido[3,4,5:m,n]thioxanthene4,10-dimethylpyrido[3,4,5:m,n]thioxanthene the following compounds canbe produced by an analogous treatment: 4-chloro-l ,2,3,11b-tetrahydropyrido[3,4,5:m,n]thioxanthene l0-chloro-l ,2,3 ,llb-tetrahydropyrido[ 3 ,4,5 :m,n] thioxanthene 4-methyl-l ,2,3,1lbtetrahydropyrido[ 3,4,5 :m,n]thioxanthene-methyl-l,2,3,11b-tetrahydropyrido[3,4,5:m,n] thioxanthene4,10-dichloro-l ,2,3 ,1lb-tetrahydropyrido[3,4,5:m,n] thioxanthene4,10-dimethyl-l ,2,3,1 1b-tetrahydropyrido[3,4,5:m,n] thioxanthene.

b. The chloroform extract (A) obtained in accordance with Example 1(a)is evaporated; the residue,

without separation by chromatography, is added to a mixture of g. oflithium aluminum hydride and 100 g. of anhydrous aluminum chloride in1.5 l. of absolute ether, and boiled for 17 hours. Under ice cooling,106 g. of sodium hydroxide in 300 ml. of water is added to the reactionmixture; the latter is vacuum-filtered from the precipitated granulatedaluminum hydroxide, washed with ether, and the hydrobromide isprecipitated with alcoholic hydrobromic acid, thus obtaining 1,2,3,11b-tetrahydropyrido[3,4,5:m,n]thioxanthene hydrobromide, m.p. 305.

Analogously, the following compounds can be prepared from the otherstarting substances mentioned in Example 1(a):

4-chloro-1,2,3 ,1 1b-tetrahydropyrido[ 3,4,5:m,n]thioxanthene(hydrobromide, m.p. 309-3 10) 10-chloro-l,2,3 ,l lb-tetrahydropyrido[3,4,5:m,n] thioxanthene 4-methyl-l ,2,3,1 lbtetrahydropyrido[3,4,5:m,n]thioxanthene 10-methyl-l ,2,3 ,1lb-tetrahydropyrido[3 ,4,5:m,n] thioxanthene 4,10-dichloro-l ,2,3 ,llb-tetrahydropyrido[3,4,5 :m,n] thioxanthene 4,10-dimethyl-l ,2,3,1lb-tetrahydropyrido[ 3,4,5:m,n] thioxanthene EXAMPLE 3 22.3 g. of2-methyl-4-phenyl-tetrahydroisoquinoline hydrobromide (m.p. 222;obtainable by cyclization of N-formyl-2,2-diphenyl-l-aminoethane withpolyphosphoric acid, subsequent hydrogenation on Raney nickel, andmethylation with formaldehyde/formic acid), 12 g. of sulfur dichloride,and 16 g. of anhydrous aluminum chloride are agitated in 500 ml. ofcarbon disulfide for 12 hours at 30. Then, the reaction mixture ispoured on ice and hydrochloric acid; the organic phase is separated, andtartaric acid is added to the acidic aqueous phase. After the additionof dilute solution of sodium hydroxide, the reaction solution isextracted with ether, dried over sodium sulfate, and, withmethanesulfonic acid, 2-methyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene methanesulfonate isprecipitated, m.p. 218.

EXAMPLE 4 a. 23.5 g. of pyrido[3,4,5:m,n]thioxanthene, prepared as thelay-product according to Example 1(a), is shaken with 100 ml. ofmethanol and 5 g. of Raney nickel in an autoclave at 120 and 180atmospheres of hydrogen pressure. After the absorption of 0.2 mol ofhydrogen, the reaction mixture is vacuum-filtered from the catalyst,and, by the addition of ethereal hydrobromic acid,l,2,3,11b-tetrahydropyrido[3,4,5 :m,n]thioxanthene hydrobromide, m.p.305, is precipitated.

b. 11.6 g. of pyrido[3,4,5:m,n]thioxanthene is mixed in nitromethanewith 5 ml. of methyl iodide and stirred for 15 hours at Afterevaporation, the mixture is reprecipitated from ethanol/water, anddried, thus obtaining pyrido[3,4,5:m,n]thioxanthene-2-methoiodide, m.p.243-245; the latter compound is dissolved in 50 ml. of methanol and,after the addition of 3 g. of Raney nickel, hydrogenated in an autoclaveat 50 and 50 atmospheres of hydrogen pressure. When the hydrogenpressure does not drop any more, the reaction mixture is vacuum-filteredand precipitated with ethereal hydrobromic acid.

After reprecipitation from methanol/ether and drying, 2-methyl-l ,2,3 ,llb-tetrahydropyrido[3 ,4,5 :m,n]t

hioxanthene hydrobromide is obtained, m.p. 24l242 The preceding examplescan be repeated with similar success by substituting the generically andspecifically described reactants and/or operating conditions of thisinvention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages. andconditions.

What is claimed is:

l. A l,2,3,llb-tetrahydropyrido[3,4,5:m,n]thioxanthene of the formula 5.A compound of claim 1,2-ethyl-l,2,3,1lbtetrahydropyrido[3,4,5:m,n]thioxanthene.

6. A compound of claim 1,2-n-propyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene.

7. A compound of claim 1, 2-isopropyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene.

8. A compound of claim 1,2-n-butyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene 9. A compoundof claim 1, 2-isobutyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene.

10. A compound of claim 1,4-methyl-l,2,3,llbtetrahydropyrido[3,4,5:m,n]thioxanthene.

1. A 1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene of the formula 2.1,2,3,11b-Tetrahydropyrido(3,4,5:m,n)thioxanthene of claim 1 wherein Xand Y are H.
 3. A compound of claim 1,1,2,3,11b-tetrahydropyrido-(3,4,5:m, n)thioxanthene.
 4. A compound ofclaim 1, 2-methyl-1,2,3,11b-tetrahydropyrido(3, 4,5:m,n)thioxanthene. 5.A compound of claim 1, 2-ethyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 6. A compound of claim 1,2-n-propyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 7. Acompound of claim 1,2-isopropyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 8. Acompound of claim 1,2-n-butyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene
 9. Acompound of claim 1,2-isobutyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 10. Acompound of claim 1,4-methyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 11. Acompound of claim 1,2,4-dimethyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 12. Acompound of claim 1,2,10-dimethyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 13. Acompound of claim 1,4,10-dimethyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.
 14. Acompound of claim 1,2,4,10-trimethyl-1,2,3,11b-tetrahydropyrido(3,4,5:m,n)thioxanthene.